CORE A PROJECT SUMMARY Vascular diseases, and hypertension remains a major cause of mortality in the US. Furthermore, individuals with metabolic syndromes are at an even greater risk of sequelae, such as a heart attack. While we have learned significant information over the years on some of the factors that contribute to vascular disease, we have large gaps in understanding about how specific cell types are recruited or activated in vascular lesions, atherosclerosis, crosstalk between cell types, regulation of vascular tone, and how these might be altered by metabolic conditions such as obesity. This overall program project addresses the intricate functions of key membrane channel, Panx1, which link many of these steps (both in physiology and pathology); Our studies over the ongoing funding period has already suggest that these channels are 'druggable' and can be relevant hypertesion. The focus of this PO1 application is to understand the role of Pannexin channels in vascular physiology and inflammation. Project 1 will study how Panx1 regulates inflammation in different tissue contexts. Project 2 will investigate Panx1 expression in the vascular smooth muscle cells affects hypertension. Project 3 will address the role of Panx1 in cellular crosstalk in the context of diet-induced cadiometabolic syndrome. Project 4 will address the mechanistic details of pannexin channel function using a variety of approaches. The Mouse Core B will provide support for the overall animal studies, while the Cell Physiology Core Cwill help with pannexin channel analysis in different cell types of relevance. The purpose of this Administrative Core (Core A) is to coordinate the different parts of this PPG by providing scientific administration, grant and fiscal management, statistical and computer/data support, and overall coordination of internal and external scientific advisory meetings.